The statistical risk of dying from lung cancer in the United States has doubled in the past thirty years for male cigarette smokers and has quadrupled for female cigarette smokers. Lung cancer has now displaced cardiovascular disease as the single most important cause of excess mortality among smokers. Yet, about 50 million Americans continue to smoke.
The benefits for smoking cessation are many, and are summarized in a publication entitled "The Health Benefits of Smoking Cessation: A Report of the Surgeon General, 1990", available from the Office on Smoking and Health, Center for Disease Control, Rockville, Md. Among the benefits summarized are that within twenty-four hours the chance of a heart attack decreases, within about two weeks to three months lung function increases up to thirty percent, and in one year the excess risk of coronary heart disease becomes half that of a smoker.
Glassman et al. in an article entitled, "Cigarette Craving, Smoking Withdrawal, and Clonidine," Science, 226, pp. 864-866 (November 1984), describes the craving developed for the tension-reducing drug, nicotine, in the absence of the drug and attributes the craving to the habituated user's experience of a rebound dysphoria. The habituated user thus seeks the drug to eliminate that dysphoria in order to treat, or relieve, craving when the person is attempting to abstain from or is reducing nicotine intake.
Smoking cessation programs often address both the physiological (biochemical) factor and the psychological factor. Recently, "nicotine-releasing patches" have been highly advertised, and are presumably useful by maintaining a nicotine-habituated patient on nicotine while addressing the psychological factor. Methods that maintain a patient on nicotine do not provide a long term solution to the problem. For example, there are now a number of patients addicted to nicotine containing gum, some of whom are seeking treatment for their new or substitute addiction.
Glassman et al., Science, 226, pp. 864-866 (1984) describe use of clonidine or alprazolam in diminishing withdrawal symptoms when fifteen heavy smokers abstained from cigarettes. The authors suggest that noradrenergic activity may be a common feature in the pathophysiology of withdrawal and that a special relationship may exist between central noradrenergic activity and craving. The authors noted that previous studies of smoking withdrawal syndrome had shown that craving is the most consistently observed withdrawal symptom.
U.S. Pat. No. 4,788,189, issued Nov. 29, 1988, inventor Glazer, suggests administering clonidine hydrochloride with an imipramine derivative in a method to treat smoking withdrawal symptoms. Clonidine is clinically used as an antihypertensive while imipramine is an antidepressant. However, recent studies suggest that the side effects of clonidine (largely anticholinergic) make it unacceptable.
U.S. Pat. No. 4,555,397, issued Nov. 26, 1985, inventor Bachynsky, describes subcutaneously injecting a patient during an initial office visit with a composition containing atropine, scopolamine, and chlorpromazine. Following the initial office visit and treatment, the patient is placed upon dosages of predominately centrally acting anticholinergic drugs (such as scopolamine by patch administration).
Atropine and scopolamine are alkaloids that block the action of acetylcholine at muscarinic receptors to produce antispasmodic, antisecretory, and antiparkinsonism actions. Scopolamine (sometimes also called "hyoscine") is a powerful suppressant of salivation (as is atropine), and is effective in the prevention and control of motion sickness.
Physostigmine (sometimes called "eserine") is an inhibitor of acetylcholine metabolism (by inhibiting the enzyme acetylcholinesterase) and is an antagonist of scopolamine. Since the action of acetylcholine is terminated by its rapid hydrolysis into choline and acetic acid, acetylcholinesterase inhibitors prolong or mimic the action of the neurotransmitter, acetylcholine.
Acetylcholine is released into synapses where it behaves as a neurotransmitter that associates with macromolecular receptors. The association of acetylcholine with its receptors initiates a physiological response, probably by opening membrane ion channels. The acetylcholine receptors appear to be of two general subtypes. One subtype appears to have nicotine as an agonist (that is, the nicotine molecule appears to fit into the one subtype of acetylcholine receptor). For example, the nicotinic effect of acetylcholine can be revealed when its degradation by acetylcholinerase is inhibited, as is discussed by Vidal and Changeux, Neuroscience, 29 (2), pp. 261-270 (1989). The other general subtype of acetylcholine receptors is muscarinic. Muscarine is an alkaloid that mimics the action of acetylcholine on muscarinic receptors.
Activation of cholinergic receptors results in bradycardia, increased secretion (e.g. salivary and sweat), gastrointestinal contractions, and other symptoms. Hypotensive, cardiac inhibitory effects caused by low doses of acetylcholine are similar to those produced by muscarine and appear to be mediated via muscarinic acetylcholinase receptors at postganglionic parasympathetic terminals, whereas effects at autonomic ganglion and skeletal neuromuscular junctions result from nicotinic acetylcholine receptors.